Abstract
Cisplatin and its analogs are among the most widely used chemotherapeutic agents against various types of cancer. It is known that cisplatin can activate epidermal growth factor receptor (EGFR), which may provide a survival benefit in cancers. Tetrathiomolybdate (TM) is a potent anti-cancer and anti-angiogenic agent and has been investigated in a number of clinical trials for cancer. In this study, we explore the therapeutic potential of TM on cisplatin-mediated EGFR regulation. Our study shows that TM is not cytotoxic, but exerts an anti-proliferative effect in ECC-1 cells. However, TM treatment prior to cisplatin markedly improves cisplatin-induced cytotoxicity. TM suppressed cisplatin-induced activation of EGFR while potentiating activation of p38; the activation of p38 signaling appeared to promote cisplatin-induced EGFR degradation. These results are in contrast to what we saw when cells were co-treated with cisplatin plus an EGFR tyrosine kinase inhibitor, where receptor activation was inhibited but receptor degradation was also blocked. Our current study is in agreement with previous findings that TM may have a therapeutic benefit by inhibiting EGFR activation. We furthermore provide evidence that TM may provide an additional benefit by potentiating p38 activation following cisplatin treatment, which may in turn promote receptor degradation by cisplatin.
Highlights
Cisplatin and its analogs are among the most widely used chemotherapeutic agents against various types of cancer
mitogen-activated protein kinase (MAPK) are serine/threonine protein kinases that consist of three distinct subgroups including p38 kinase, c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinase (ERK). p38 and JNK signaling regulate stress-mediated apoptosis, and their activation is known to be pivotal for cisplatin-induced cytotoxicity[1]
In order to measure the effects of drugs on apoptosis quantitatively we carried out the caspase-3/7 activity assay. This assay revealed that ECC-1 cells exposed to combinatorial treatment had a 1.9-fold increase in apoptosis over cells exposed to cisplatin alone (Fig. 1E)
Summary
TM inhibits cell proliferation and sensitizes cancer cells to cisplatin. Anti-proliferative effects of TM have been reported[28,29,32]. The level of EGFR was clearly decreased when cells were treated with both TM and cisplatin, which was accompanied by the appearance of p38 activation (Fig. 6A), suggesting that TM-induced p38 potentiation may trigger receptor degradation following short-term cisplatin exposure. Similar to what we observed in ECC-1 cells (Fig. 1E), we saw that SiHa and A2780CIS cells exposed to the combination treatment of TM and cisplatin showed a respective 4.6- or 4.3-fold increase in apoptosis compared to those only treated with cisplatin (Fig. 6C). These results suggest that TM may be an effective adjuvant therapy in multiple tumor types, including. Our data here suggest that TM may possess a therapeutic benefit by potentiating p38 activation for the treatment of cancer
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